Researchers identify the first step in allergic reactions

Scientists at Duke-NUS Medical School have identified how the first domino falls after a person encounters an allergen, signalling a new strategy for the prevention of life-threatening allergic reactions. Their discovery has been published in the journal Nature Immunology.

It is well established that when mast cells, a type of immune cell, mistake a harmless substance (such as a peanut or dust mite) as a threat, they release an immediate first wave of bioactive chemicals against the perceived threat. When mast cells — which reside under the skin, around blood vessels and in the linings of the airways and the gastrointestinal tract — simultaneously release their pre-stored load of bioactive chemicals into the blood, instant and systemic shock can result, which can be lethal.

Now, Duke-NUS researchers have discovered that the release of particulate mast cell granules, which contain these bioactive chemicals, is controlled by two members of an intracellular multiprotein complex called the inflammasome. Until now, these inflammasome proteins were only known to spontaneously assemble within immune cells to secrete soluble chemicals to alert other parts of the immune system upon detection of an infection.

“We discovered that the inflammasome components played a surprisingly crucial role in transporting particulate mast cell granules — which are typically packed in the cell centre — to the cell surface, where they are released,” said Professor Soman Abraham, who led this research when working in Duke-NUS’s Emerging Infectious Diseases Programme. “This surprising discovery gives us a precise target where we can intervene to prevent the cascade of events initiated in mast cells that leads to anaphylactic shock.”

Abraham and his team’s eureka moment came while observing mice whose mast cells lacked either of the two inflammasome proteins, NLRP3 or ASC. When these animals were exposed to allergens, they failed to experience anaphylactic shock. However, anaphylactic shock was observed when mast cell NLRP3 and ASC proteins assembled and bound to individual intracellular granules, forming a complex the researchers call granulosome, facilitating the granules’ movement along tracks formed by the cytoskeleton within the mast cell — akin to hooking them onto a set of ‘rail tracks’.

“Upon mast cell activation, we observed rapid granule movement on dynamic tracks known as microtubules to the cell membrane, where these granules were promptly released from the cell,” said co-first author Dr Pradeep Bist, a principal research scientist with the Emerging Infectious Diseases Programme. “However, in mast cells deficient in either NLRP3 or ASC proteins, we found no sign of intracellular granule movement and none of these granules were released.”

Having demonstrated the trafficking role of NLRP3 and ASC, the team turned to known inflammasome inhibitors to test whether they could prevent this event from taking place. Using an inflammasome-blocking drug very similar to those undergoing clinical trials for chronic inflammatory diseases, called CY-09, they administered the therapy to mice before introducing an allergen. They found that in their preclinical model, they were able to effectively prevent anaphylactic shock with this drug.

“It was noteworthy that by employing a drug that specifically blocked inflammasome protein activity, we were able to selectively block the release of mast cells’ pre-stored chemicals without impacting other potentially beneficial activities of mast cells,” said Dr Andrea Mencarelli, who co-first authored the paper while working in the Emerging Infectious Diseases Programme.

While not a cure, this could offer people living with severe allergies a new tool to prevent the onset of a potentially traumatic reaction. Currently, emergency treatments are taken in the immediate aftermath of the first symptoms developing, but these treatments need to be administered within a narrow window of time to be effective and also have severe side effects.

“I could see this bringing peace of mind to parents of children with severe food allergies when they encounter situations where they can’t be sure whether there’s an exposure risk,” said Abraham, whose team is now working on optimising the dosage and frequency of use of the drug to achieve the best protective effects against anaphylactic shock.

“While we don’t want to deactivate this part of the immune system for prolonged periods, this could potentially provide short-term protection.

“After this, we hope to do the same for asthma and allergic skin reactions.”

Image credit: iStock.com/monticelllo